The leading hypothesis for the pathophysiology of schizophrenia is that some or all components of the ascending dopamine projection from midbrain to telencephalon are overactive in schizophrenics. The most compelling data for the involvement of dopamine (DA) in schizophrenia are clinically based in that the drugs found most successful in the treatment of schizophrenia are DA antagonists. Conversely, "schizophrenia-like" symptoms can result from relatively high and/or chronic doses of psychomotor stimulants such as amphetamine. Although some preclinical data have provided support for the DA hypothesis, very few data have emerged that allow for an interpretation of the DA hypothesis that is based on synaptic organization and precise neural circuitry. This component is directed at furnishing data on the regional, laminar, cellular, and synaptic organization of the DA innervation of cerebral cortex in non-human primate and humans brains. More specifically, we will center our efforts on the characterization of the target cell of the dopaminergic innervation of neocortex. Our detailed light microscopic analyses of the dopaminergic innervation of primate neocortex have already offered some clues as to the likely cellular targets of the DA fibers. The light microscopic analysis of frontal lobe has been completed, and a similar analysis of temporal lobe will be a distribution will be complemented by both an electron microscopic analysis of synapse distribution, and a light microscopic analysis of D2 receptor distribution by both in situ hybridization and immunohistochemistry. In addition to these detailed analyses of the distribution of pre- and post-synaptic DA markers, cell-loading in combination with axonal transport and immunohistochemical studies will be used to determine the specific target cells of the DA projection, and where appropriate, the efferent target of the specified target cell. These studies will be extended to the analysis of both normal and schizophrenic human brain and will allow for a neuropathologic analysis that is directed at the elucidation of specified cells, circuits and synapses that constitute or area influenced by the DA innervation of neocortex.